Cancer is caused by the genetic abnormality due to radiation, ultraviolet, carcinogen, virus, and the like. The number of deaths due to cancer is increasing yearly, and currently cancer is the top cause of death in Japan. The means for treating such cancer include, for example, an antitumor drug, a surgery, a radiation therapy, and an immunotherapy, in which the therapy with an antitumor drug is the most important as a medical therapy. Major antitumor drugs act on any of a metabolism of nucleic acid precursor, a DNA synthesis, an RNA synthesis and a protein synthesis. However, such metabolic process is done not only in a cancer cell, but also in a normal cell. Thus, many antitumor drugs act on a cancer cell as well as a normal cell, and the action on a normal cell causes various side-effects.
Recently, a molecular target drug which is a new type of antitumor drugs is used. The molecular target drug is a drug designed to target a molecular which is specifically expressed in each cancer. Accordingly, it is thought that a molecular target drug is more specific for cancer compared with conventional antitumor drugs, and has low side-effects. A molecular target drug, however, has other problems that new side-effects happen and the choice of drugs is restricted, though hitherto-known side-effects are reduced. The above-mentioned antitumor drugs have been clinically used for treating cancer or life-sustaining a patient suffering from cancer, but the drugs have many unresolved problems including the above-mentioned side-effects. Thus, the development of a new anti-cancer drug is a still important challenge.
The research in recent years has clarified that a cancer stem cell (CSC) having self-renewal capacity exists, which is closely related to the malignant progression of cancer. Each CSC for almost all human major cancers such as breast cancer, colon cancer, lung cancer, and hematologic malignancy has been already identified (Non-Patent Reference 1). The biological property of a CSC is very different from that of a normal cancer cell differentiated from a CSC. It shows that a CSC plays a large role in the continuing proliferation of malignant tumor, the metastasis of cancer, the relapse and the resistance for an antitumor drug. The conventional therapy which targets a normal cancer cell constituting a large part of tumor mass is expected to reduce the size of tumor, but not expected to bring in a meaningful survival effect unless also targeting CSC simultaneously. Thus, it is very prospective to target a CSC to seek a new therapy for cancer (Non-Patent Reference 2). One of the properties of a CSC is to have self-renewal capacity (Non-Patent Reference 3). A reliable method established as a method of evaluating the cell self-renewal capacity is a measurement of the sphere-forming ability of cancer cells, which is done under non-adherent state in the absence of serum (Non-Patent Reference 4). A compound inhibiting the growth of cancer cells which are non-CSCs and suppressing the sphere-forming ability of cancer cells can be very hopeful as a new antitumor drug.
The quinone derivatives which are isolated from extracts of Bignoniaceae tabebuia plant of the following formulae:
wherein R1, R2 and R3 are H; R1 and R3 are H, R2 is OH; R1 is OH, R2 and R3 are H; R1 and R2 are H, R3 is COCH3; or R1 and R2 are H, R3 is COC(CF3)OCH3)CH5, have been already known to have an anti-tumor activity (Non-Patent Reference 5). However, a quinone derivative having more potent anti-tumor activity has been desired.
In the past, the following compounds described in Patent References 1 to 4 for example have been known as a naphtho[2,3-b]furan derivative. Patent Reference 1 discloses the following compound:
wherein R is —OR′, —R′, —CO—R′, or —OCO—R′, and R′ is a hydrogen atom, an alkyl group and/or a hydroxyalkyl group.
Patent Reference 2 discloses the following compound:
wherein X is —O—, —S—, or —NR8—; R1 and R2 are independently H, a C1-C4 alkyl, and the like; R3 is —OR9; R4 is H, a halogen or —OR9; R5 and R6 are independently defined as R1 and R2; R8 is H, a straight or branched chain C1-C18 alkyl, phenyl or benzyl which is un-substituted or substituted with a C1-C4 alkyl or a C1-C4 alkoxy; R9 is hydrogen, a C1-C12 alkyl, or the like; R10 is H, a C1-C18 alkyl, or the like; and R11 is H, a C1-C4 alkyl or phenyl.
Patent Reference 3 discloses the following compound:
wherein R is a C1-C6 alkyl.
Patent Reference 4 discloses the following compound:
wherein X is O or S, R1 is hydrogen, halogen, cyano, nitro, CF3, OCF3, alkyl or substituted alkyl, or the like, R3 is hydrogen, cyano, CF3. OCF3, alkyl or substituted alkyl, and the like, R7 is hydrogen, halogen, cyano, nitro, CF3, OCF3, alkyl or substituted alkyl, or the like, n is 1 to 4, provided that when R3 is not NRbNc, then R7 is not hydrogen and at least one of R1 and R7 is halogen, an aryl or substituted aryl. However, Patent References 1 to 4 never disclose the present compound of formula (1).